A strong body of evidence implicates cerebrovascular amyloid deposition (cerebral amyloid angiopathy or CAA) as an important independent contributor to cognitive impairment in the elderly, most likely by effects on vessel function. Unlike other common vascular risk factors, CAA remains entirely unbeatable. We propose a prospective longitudinal study using multiple state-of-the-art imaging modalities to define the mechanisms by which CAA affects cognition and vessel function. The proposed studies focus on patients with CAA related intracerebral hemorrhage, the one clinical population in which CAA can be non-invasively recognized during life. In Specific Aim #1, we will perform serial MRI imaging on patients with CAA to identify areas of progressive white matter damage detectable by FLAIR or diffusion-tensor techniques. These studies will assess both risk factors for progression of white matter damage in CAA and the clinical manifestations of white matter changes. Specific Aim #2 proposes functional transcanial Doppler studies aimed at measuring alterations in physiologic cerebrovascular reactivity in CAA. Both white matter damage and cerebrovascular reactivity will be analyzed for their effects on risk of cognitive decline, appearance of depressive symptoms, loss of functional skills, and death. In Specific Aim #3, we will determine whether vascular amyloid can be non-invasively detected and quantified by PET scan using the lipophilic amyloid-binding molecule Pittsburgh Compound-B, potentially offering the first opportunity to broaden the study of CAA-related vascular dysfunction to the general elderly population at risk for CAA. This proposal builds on the Principal Investigator's expertise in the diagnosis, genetics, clinical course, and pathophysiology of CAA and his group's well-characterized prospective longitudinal cohort of patients diagnosed with CAA. Successful completion of this study will represent a key step towards developing diagnostic markers, outcome markers, and candidate treatments for future trials aimed at preventing CAA-related cognitive impairment.